Human immunodeficiency virus (HIV) codes an aspartic protease which is indispensable for proper virion assembly and maturation. This virus- specific protease mediates crucial proteolytic processing of certain viral protein precursors at a late stage in the replication of HIV. This process is essential for the maturation of newly-assembled virus particles into infectious virions. Indeed, inactivation of HIV protease by site-directed mutation in the protease gene results in the production of immature, non- infectious viral particles. The design of HIV-1 protease inhibitors based on the transition state mimetic concept has led to the generation of a variety of peptide derivatives highly active against viral replication in vitro. Two-fold (C2) symmetry-based inhibitors of HIV protease represent another unique class of potent HIV protease inhibitors which were designed to correspond to the C2 symmetric active site structure of the HIV protease homodimer. One such inhibitor, A77003, which has considerable aqueous solubility, has been shown to have a broad-spectrum of antiretroviral activity against both HIV-1 and HIV-2 types, including AZT- insensitive HIV-1 variants in vitro in a variety of human target cells.